Radiometal complex compositions

Abstract

The present invention relates to stabilised technetium and rhenium metal complex compositions comprising a radioprotectant and a radiometal complex of a tropane-tetradentate chelating agent conjugate, wherein the radiometal complex is neutral. Radiopharmaceuticals comprising the stabilised metal complex compositions, and kits for the preparation of the radiopharmaceuticals are also described.

1 . A stabilised composition which comprises: 
 (i) a metal complex of a radioactive isotope of technetium or rhenium chelated to a conjugate, wherein said conjugate comprises a tetradentate chelating agent conjugated to a tropane, and said tetradentate chelating agent forms a neutral metal complex with said radioactive isotope of technetium or rhenium;    (ii) at least one radioprotectant.    
     
     
         2 . The stabilised composition of  claim 1 , wherein the conjugate is of Formula Ia:  
         [{tropane}-(A) n ] m -[tetradentate chelating agent]  (Ia)  where:    -(A) n - is a linker group wherein each A is independently —CR 2 —, —CR═CR—, —C≡C—, —CR 2 CO 2 —, —CO 2 CR 2 —, —NRCO—, —CONR—, —NR(C═O)NR—, —NR(C═S)NR—, —SO 2 NR—, —NRSO 2 —, —CR 2 OCR 2 —, —CR 2 SCR 2 —, —CR 2 NRCR 2 —, a C 4-8  cycloheteroalkylene group, a C 4-8  cycloalkylene group, a C 5-12  arylene group, or a C 3-12  heteroarylene group;    R is independently chosen from H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxyalkyl or C 1-4  hydroxyalkyl;    n is an integer of value 0 to 10; and,    m is 1, 2 or 3.    
     
     
         3 . The stabilised composition of  claim 1 , where the tropane is a phenyl tropane of Formula III:  
       
         
           
           
               
               
           
         
         where:  
         R 1  is H, C 1-4  alkyl, C 1-4  alkenyl or C 1-4  fluoroalkyl; 
 R 2  is CO 2 R 5 , CON(R 5 ) 2 , COR 5  or C 1-4  alkyl, where each R 5  is independently H or C 1-3  alkyl;  
 R 3  and R 4  are independently H, Cl, Br, F, I, CH 3 , CF 3 , NO 2 , OCH 3  or NH 2 .  
 
       
     
     
         4 . The stabilised composition of  claim 1 , wherein the radioactive isotope of technetium is  99m Tc.  
     
     
         5 . The stabilised composition of  claim 1 , wherein the tetradentate chelating agent is conjugated to either the 2- or the 8-position of the tropane.  
     
     
         6 . The stabilised composition of  claim 5 , wherein the tetradentate chelating agent is conjugated to the 2-position of the tropane.  
     
     
         7 . The stabilised composition of  claim 1 , wherein the tetradentate chelating agent has a donor set chosen from: 
 (i) N 2 S 2 ;    (ii) N 3 S;    (iii) diaminedioxime, or    (iv) amidetriamine.    
     
     
         8 . The stabilised composition of  claim 1 , wherein the tetradentate chelating agent has an N 2 S 2  diaminedithiol donor set.  
     
     
         9 . The stabilised composition of  claim 1 , wherein the radioprotectant comprises ascorbic acid, para-aminobenzoic acid or gentisic acid, or a salt thereof with a biocompatible cation.  
     
     
         10 . The stabilised composition of  claim 9 , wherein the radioprotectant comprises ascorbic acid or a salt thereof with a biocompatible cation.  
     
     
         11 . The stabilised composition of  claim 10 , wherein the radioprotectant comprises ascorbic acid or sodium ascorbate.  
     
     
         12 . The stabilised composition of  claim 1  wherein the metal complex comprises the radioactive technetium isotope  99m Tc; 
 the tetradentate chelating agent has an N 2 S 2  diaminedithiol donor set and is conjugated to the 2-position of a phenyl tropane of Formula III;    and the radioprotectant comprises ascorbic acid or a salt thereof with a biocompatible cation.    
     
     
         13 . The stabilised composition of  claim 12 , wherein the metal complex has the Formula:  
       
         
           
           
               
               
           
         
       
     
     
         14 . A precursor composition useful in the preparation of the stabilised composition of  claim 1 , said precursor composition comprising: 
 (i) the conjugate of Formula Ia;      [{tropane}-(A) n ] m -[tetradentate chelating agent]  (Ia)  where:    -(A) n - is a linker group wherein each A is independently —CR 2 —, —CR═CR—, —C≡C—, —CR 2 CO 2 —, —CO 2 CR 2 —, —NRCO—, —CONR—, —NR(C═O)NR—, —NR(C═S)NR—, —SO 2 NR—, —NRSO 2 —, —CR 2 OCR 2 —, —CR 2 SCR 2 —, —CR 2 NRCR 2 —, a C 4-8  cycloheteroalkylene group, a C 4-8  cycloalkylene group, a C 5-12  arylene group, or a C 3-12  heteroarylene group;    R is independently chosen from H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxyalkyl or C 1-4  hydroxyalkyl;    n is an integer of value 0 to 10; and,    m is 1, 2 or 3.      (ii) the radioprotectant of  claim 1 .    
     
     
         15 . The precursor composition of  claim 14 , where the tropane of the conjugate of Formula Ia is a phenyl tropane of Formula III.  
     
     
         16 . The precursor composition of  claim 14  where the chelator conjugate is of Formula IV:  
       
         
           
           
               
               
           
         
         where P 1  and P 2  are independently H or a thiol protecting group.  
       
     
     
         17 . The precursor composition of  claim 16 , where P 1  and P 2  are both H.  
     
     
         18 . A radiopharmaceutical which comprises the stabilised composition of  claim 1  together with a biocompatible carrier, in a form suitable for mammalian administration.  
     
     
         19 . The radiopharmaceutical of  claim 18 , where the radiopharmaceutical is provided in a syringe.  
     
     
         20 . The radiopharmaceutical of  claim 18 , where the radiopharmaceutical is provided in a vial fitted with a closure, wherein said closure is suitable for maintaining sterile integrity when punctured with a needle.  
     
     
         21 . A kit for the preparation of the radiopharmaceutical of  claim 18 , which comprises: 
 (i) the conjugate of Formula (Ia) or a salt of said conjugate with a biocompatible counterion;    (ii) at least one radioprotectant;    (iii) a biocompatible reductant.    
     
     
         22 . The kit of  claim 21 , where the radioprotectant comprises ascorbic acid, para-aminobenzoic acid or gentisic acid, or a salt thereof with a biocompatible cation.  
     
     
         23 . The kit of  claim 21 , where the biocompatible reductant comprises stannous.  
     
     
         24 . A method of preparation of the radiopharmaceutical of  claim 18 , which comprises formation of the metal complex of  claim 1  in a biocompatible carrier in a form suitable for mammalian administration by either: 
 (i) reaction of a radioactive isotope of technetium or rhenium with the precursor composition useful in the preparation of composition of  claim 1 , said precursor composition comprising the conjugate of Formula Ia and the radioprotectant of  claim 1 , wherein the reaction takes place in a biocompatible carrier in a form suitable for mammalian administration; or    (ii) forming the metal complex of  claim 1  in a biocompatible carrier in a form suitable for mammalian administration, and then subsequently adding an effective amount of at least one radioprotectant.    
     
     
         25 . The method of  claim 24 , where the metal complex comprises the conjugate of Formula Ia.  
     
     
         26 . The method of  claim 24 , where the radioprotectant comprises ascorbic acid, para-aminobenzoic acid or gentisic acid, or a salt thereof with a biocompatible cation.  
     
     
         27 . Use of the radiopharmaceutical of  claim 18  in a method of diagnostic imaging of the mammalian body.  
     
     
         28 . A method of diagnostic imaging of the mammalian body which comprises imaging a mammal which had previously been administered with the radiopharmaceutical of  claim 18.